Combination Therapies Targeting Alk-Aberrant Neuroblastoma in Preclinical Models

Abstract

Background: ALK activating mutations are identified in approximately 10% of newly diag-nosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation ALK inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single agent treatment has been reported and therapies that improve the response duration are urgently required. We stud-ied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. Aims: To study the preclinical activity of ALK inhibitors alone and in combination with chemotherapy or idasanutlin. Methods: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemo-therapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and pa-tient derived xenografts (PDX). Results: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only ob-served in the ALK-amplified PDX model with the highest ALK expression. In this PDX lorla-tinib combined with idasanutlin resulted in complete tumor regression and significantly de-layed tumor regrowth. Conclusion: Our study suggests that in neuroblastoma, high ALK expression could be asso-ciated with response to lorlatinib and either chemotherapy or idasanutlin. The synergy be-tween MDM2 inhibition and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

“…Several of our models already have been used for preclinical explorations and were included in publications demonstrating the proof-of-concept for their relevance. Among those were Burkitt lymphoma 40 , anaplastic large cell lymphoma 41 , neuroblastoma [42][43][44] , Ewing sarcoma 45 , rhabdomyosarcoma 46,47 and acute lymphatic leukemia 48 PDX models.…”